August 2009

August 29, 2009

The complex choreography
of chromosome segregation in anaphase is split into two processes: Anaphase A
in which sister chromatids move to opposite spindle poles and Anaphase B in
which the spindle elongates.The latter
occurs when overlapping, antiparallel microtubules that constitute the ‘central
spindle’ or spindle midzone slide past each other.The microtubule-associated protein (MAP)
PRC1/Ase1 is required for midzone assembly and stability of the anaphase
spindle (Khmelinskii et al., 2007;
Schuyler et al., 2003).In work
published in The JCB, Scheibel and
colleagues (Khmelinskii et al., 2007) showed that in budding yeast Ase1
dephosphorylation by the phosphatase Cdc14 is important for midzone formation
and spindle elongation.

Image from Khmelinskii et al. (2007).Ase1 (green)localizes to the spindle midzone
in anaphase

In the August
issue of Developmental Cell,
Khmelinskii et al. (2009) present the next step in this story.They show that Ase1 dephosphorylation
promotes its interaction with the kinesin Cin8 thereby recruiting Cin8 to the
central spindle where it drives spindle elongation.This function of Ase1 appears to be conserved
in fission yeast as shown by Fu et al. (2009) in the same issue. These studies,
together with previous work, show how the timing of Anaphase A and B are
coordinated.In early mitosis, Ase1 is
phosphorylated by Cdk1 thereby preventing spindle elongation.At the metaphase to anaphase transition, separase—which
cleaves cohesin to promote sister chromatid separation—activates Cdc14 through
the FEAR network.Cdc14 dephosphorylates
Ase1 which moves to the spindle midzone and recruits, in addition to many other
proteins, Cin8, which slides antiparallel microtubules apart to promote spindle
elongation.

August 26, 2009

A little bit later than usual, but here's a quick rundown of some of the highlights from the latest issue of the JCB.

Our main cover story this time around is a study from Hall et al. investigating the regulation of a large, chromatin-binding RNA called XIST. XIST coats and inactivates one X chromosome early in female mammalian development, but little is known about how the RNA associates with the chromatin and what regulates the process. Hall et al. exploit the fact that XIST is temporarily released from the X chromosome during mitosis to manipulate its localization in vivo. Through this approach, the researchers discover that the mitotic kinase Aurora B regulates XIST's association with chromatin. You can read more about the study, and why the group's approach should help other researchers studying chromatin-RNA interactions, in my 'In Focus' article here.

Elsewhere, two papers dissect the roles that type V myosins play in transporting organelles around the cell. Jung et al. find that a myosin called myoJ drives the spreading of contractile vacuoles around the actin-rich cortex of dictyostelia, helping the cells discharge excess rain water and avoid osmotic stress. It's a really fascinating process, and Jung et al.'s videos are fantastic - look out for a forthcoming biosights video podcast that describes the story in more detail. In the meantime, you can find a short summary of the work right here. Meanwhile, a myosin called Myo2 helps yeast partition peroxisomes into their daughter cells. Fagarasanu et al. explore how this is regulated in both time and space by the cell cycle, and a feedback mechanism that halts further peroxisome transport once the bud has got its fair share. Again, you can read more in this summary piece.

Sticking with budding yeast, Madia et al. explore how Sch9 - a homologue of the mammalian oncogenes Akt and S6 kinase - promotes age-dependent mutations. The group - led by USC's Valter Longo - has shown in the past that yeast lacking Sch9 live much longer than wild-type cells and accumulate fewer mutations in their genome over time. Now they show why - Sch9 promotes oxidative DNA damage and an error-prone DNA repair mechanism. The results may help explain why the incidence of cancer increases with advancing age and, surprisingly, suggests that oncogenes like Akt may promote DNA damage in non-dividing, rather than dividing cells. No summary this time, but you can hear more from Valter Longo himself in our latest biobytes podcast, also out this week. Listen here, or on the player below.

Bhagatji et al. describe how GPI-linked membrane proteins get endocytosed via a clathrin and dynamin-independent pathway. By tagging proteins with an artificial membrane anchor, the researchers show that it's the steric bulk of the GPI-linked protein that determines its specific endocytosis, rather than any particular structural feature of the protein or the GPI group itself. In the image below, for example, an antibody tagged with a di16:0PEG lipid group (green) localizes to the same endocytic compartment as the GPI-linked folate receptor (red, right panel), but doesn't co-localize with the transmembrane transferrin receptor (red, left panel).

Ben Nichols has a nice summary of the group's findings, and also wins this week's award for best pun in an article's title. And finally for today, I'll point you in the direction of David Razafsky and Didier Hodzic's review of the protein complexes that link the cytoskeleton to the nuclear skeleton and govern nuclear and centrosomal dynamics. You can find that, and all the other articles in the latest JCB, on our table of contents.

August 21, 2009

Monday, August 17, 2009 marked Dr. Francis Collins’ first
day as the Director of the NIH.Dr.
Collins is perhaps best known for being the head of the Human Genome Project.With a mixture of humility and humor, Dr.
Collins spoke about his vision for the NIH to an assembly of NIH staff.You can watch his address here.In this address, he split his goals up into 5
themes: uncovering the causes of specific diseases using high-throughput
technology and multi-disciplinary approaches; translational medicine to develop
diagnostics, preventative strategies and therapeutics; health care reform;
global health; and efforts to reinvigorate and empower the biomedical
community.For the last theme, he would
like to work towards a stable funding environment and move away from the ‘feast
or famine’ scenario, which he termed destructive.He ended with a promise to focus his full energy
on his new position and reassured the audience that his personal religious
beliefs would not interfere with his title as Scientific Director of the
NIH. Image courtesy of the National Institutes of Health.

August 10, 2009

Lots to highlight in today's new issue, so let's crack straight on with it...

Our striking cover image this week shows the disruption to the microtubule network in mouse muscle fibers caused by a defect in the dystrophin gene (which models the mutation afflicting Duchenne Muscular Dystrophy patients). Prins et al. reveal that - in addition to its interactions with the actin and intermediate cytoskeletons - dystrophin also binds microtubules. As Mitch explains in his summary, this suggests that dystrophin acts as a cytolinker, connecting microtubules to the plasma membrane, just as it does with other cytoskeletal components.

Mitch has also written an In Focus article about the surprising report from Xu et al. that components of the histone H3 lysine 4 methyltransferase complex have an additional function in regulating endosomal trafficking. One component in particular, called mDpy-30, localizes to the trans-Golgi network. Knocking down mDpy-30 (or two other H3K4 methyltransferase subunits) causes a redistribution of an endosomal cargo protein, and an accumulation of recycling endosomes at cell protrusions. Mitch's summary explains why the authors think mDpy-30 might be an important regulator of cell adhesion and migration.

Nakanishi et al. investigate the more orthodox function for histone methyl transferases. They demonstrate that the trimethylation of histone H3 on lysines 4 and 79 is absolutely dependent on the prior ubiquitination of histone H2B. This dependency had been postulated before, but had recently been called into question. In an accompanying commentary, John Latham and Sharon Dent explain why Nakanishi et al.'s work is a timely confirmation of the importance of crosstalk between different modifications on different histones.

Elsewhere, Yamakoshi et al. study crosstalk between two tumor suppressors, p16Ink4a and p53. The group constructed transgenic mice that express a p16Ink4a-luciferase fusion protein under the control of p16's endogenous promoter. The group could then use bioluminescent imaging to non-invasively image the real-time expression of the tumor suppressor in living animals in response to various stresses, as you can see in the picture below.

The researchers found that p16Ink4a was induced by oncogenic stresses such as DNA damage, and this response was accelerated in mice lacking p53, suggesting that p16Ink4a expression acts as a backup to p53 and is held in check if the p53 pathway is functioning normally.

Finally for this issue, we have a couple of papers on the complex assembly of focal adhesions, by which cells attach to their surrounding extracellular matrix. Ronen Zaidel-Bar takes the "adhesome" of proteins that make up focal adhesions and examines their conservation across evolution. Zaidel-Bar finds that the adhesome largely evolved by gene duplication to produce families of related proteins that interact with different partners and therefore developed specialized functions in higher organisms. Winograd-Katz et al., meanwhile, take a systems biology approach to studying the adhesome, knocking down the different components by RNAi and conducting a multi-parametric analysis of the compromised adhesions. I shan't dwell on this any longer, as you can learn more by watching our latestbiosights video podcast:

If systems biology papers usually leave you feeling a little underwhelmed, I'll be glad to point you in the direction of an article written by yours truly, that investigates how systems biology approaches are really beginning to bear fruit in terms of understanding cell biology. It's clear that you'll be seeing a lot of important and informative papers like Winograd-Katz et al.'s in the JCB in future. If you're a traditionalist though, you'll be glad to hear that good, old-fashioned cell biology still has an important role to play in guiding systems biologists and testing their predictions. Have a read, and feel free to comment below, on this or any other articles in the latest edition of the JCB.

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